Cardiovascular disease is one of the most debilitating diseases in America. Currently, mechanisms leading to repair of developmentally abnormal or diseased hearts is unknown. Encouraging results in transplantation studies have been shown with cardiac cell replacement. However, it is not known which cell types or microenvironment will be the most efficient for cell replacement. This proposal will examine the ability of human embryonic stem (hES), NIH registry no. WA01, and embryonic germ cells (hEG) for repair or repopulation of developmentally abnormal or damaged heart models. In Aim 1, organ coculture will be used to create an environment similar to in vivo for differentiation of cardiomyocytes in embryonic day 7-12 mouse hearts. Aim 2 will examine the ability of human ES or EG cells to repopulate the cardiac stem cell niche in mice with a mutation in the Gja1 gene, which have congenital cardiac abnormalities, and also to repair heart tissue damaged by diptheria toxin to determine the role of the cardiac stem cell niche in directing hEG or hES differentiation. In Aim 3, coculture of cardiac neural crest cells with hES or hEG cells will be used to determine if these cells may also be able to direct cardiomyocyte differentiaton.